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The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine

Molecular Psychiatry volume 25, pages 48–66 (2020)Cite this article

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Abstract

Schizophrenia and bipolar disorder (BPD) are believed to share clinical features, etiological factors, and disease pathologies (such as impaired cognitive functions and dendritic spine pathology). Meanwhile, there is growing evidence of shared genetic risk between schizophrenia and BPD, despite that our knowledge of the functional risk variations and biological mechanisms is still limited. Here, we conduct summary data-based Mendelian randomization (SMR) analyses through combining the statistical data from genome-wide association studies (GWAS) of both schizophrenia and BPD and multiple expression quantitative trait loci (eQTL) datasets of the human brain dorsolateral prefrontal cortex (DLPFC) tissues. These integrative investigations identify a lead risk locus at the chromosome 3p21.1 region, which contains numerous single-nucleotide polymorphisms (SNPs) in varied linkage disequilibrium (LD) and encompasses more than 20 genes. Further analyses suggest that many SNPs at 3p21.1 are significantly associated with both schizophrenia and BPD, and even depression, and the psychiatric risk alleles at 3p21.1 are correlated with mRNA expression of multiple genes such as NEK4, GNL3, and PBRM1. We also identify a 335-bp functional Alu polymorphism rs71052682 in significant LD with the psychiatric GWAS risk SNP rs2251219, and confirm the regulatory effects of this Alu polymorphism on transcription activities. We then explore the involvement of the 3p21.1 locus in the common clinical features and etiology of these illnesses. We reveal that psychiatric risk alleles at 3p21.1 in low-to-high LD consistently predict worse cognitive functions in humans, and manipulating the gene expression (NEK4, GNL3, and PBRM1) linked with higher genetic risk could reduce the density of mushroom dendritic spines in rat primary cortical neurons, mirroring the spine pathology in the prefrontal cortex of psychiatric patients. Our results find that, although the risk alleles at 3p21.1 are in low-to-moderate LD spanning a large genomic area, their underlying biological mechanisms in psychiatric disorders likely converge. These results provide essential insights into the neural mechanisms underlying the chromosome 3p21.1 risk locus in the shared pathological and etiological features of both schizophrenia and BPD.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (31701133 to XX, 81722019 to ML, and 81871067 to HC). XX was also supported by the Chinese Academy of Sciences Western Light Program, and Youth Innovation Promotion Association, CAS. ML was also supported by CAS Pioneer Hundred Talents Program and the 1000 Young Talents Program. Data were generated as part of the PsychENCODE Consortium, supported by: U01MH103392, U01MH103365, U01MH103346, U01MH103340, U01MH103339, R21MH109956, R21MH105881, R21MH105853, R21MH103877, R21MH102791, R01MH111721, R01MH110928, R01MH110927, R01MH110926, R01MH110921, R01MH110920, R01MH110905, R01MH109715, R01MH109677, R01MH105898, R01MH105898, R01MH094714, P50MH106934, U01MH116488, U01MH116487, U01MH116492, U01MH116489, U01MH116438, U01MH116441, U01MH116442, R01MH114911, R01MH114899, R01MH114901, R01MH117293, R01MH117291, R01MH117292 awarded to: Schahram Akbarian (Icahn School of Medicine at Mount Sinai), Gregory Crawford (Duke University), Stella Dracheva (Icahn School of Medicine at Mount Sinai), Peggy Farnham (University of Southern California), Mark Gerstein (Yale University), Daniel Geschwind (University of California, Los Angeles), Fernando Goes (Johns Hopkins University), Thomas M. Hyde (Lieber Institute for Brain Development), Andrew Jaffe (Lieber Institute for Brain Development), James A. Knowles (University of Southern California), Chunyu Liu (SUNY Upstate Medical University), Dalila Pinto (Icahn School of Medicine at Mount Sinai), Panos Roussos (Icahn School of Medicine at Mount Sinai), Stephan Sanders (University of California, San Francisco), Nenad Sestan (Yale University), Pamela Sklar (Icahn School of Medicine at Mount Sinai), Matthew State (University of California, San Francisco), Patrick Sullivan (University of North Carolina), Flora Vaccarino (Yale University), Daniel Weinberger (Lieber Institute for Brain Development), Sherman Weissman (Yale University), Kevin White (University of Chicago), Jeremy Willsey (University of California, San Francisco), and Peter Zandi (Johns Hopkins University). Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692. Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: Pamela Sklar, Joseph Buxbaum (Icahn School of Medicine at Mount Sinai), Bernie Devlin, David Lewis (University of Pittsburgh), Raquel Gur, Chang-Gyu Hahn (University of Pennsylvania), Keisuke Hirai, Hiroyoshi Toyoshiba (Takeda Pharmaceuticals Company Limited), Enrico Domenici, Laurent Essioux (F. Hoffman-La Roche Ltd), Lara Mangravite, Mette Peters (Sage Bionetworks), Thomas Lehner, Barbara Lipska (NIMH).

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  1. These authors contributed equally: Zhihui Yang, Danyang Zhou, Huijuan Li

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China

    Zhihui Yang, Danyang Zhou, Huijuan Li, Xin Cai, Weipeng Liu, Lu Wang, Hong Chang, Ming Li & Xiao Xiao

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China

    Zhihui Yang, Danyang Zhou, Huijuan Li, Xin Cai, Weipeng Liu & Ming Li

  3. CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Ming Li

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  1. Zhihui Yang
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Yang, Z., Zhou, D., Li, H. et al. The genome-wide risk alleles for psychiatric disorders at 3p21.1 show convergent effects on mRNA expression, cognitive function, and mushroom dendritic spine. Mol Psychiatry 25, 48–66 (2020). https://doi.org/10.1038/s41380-019-0592-0

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